Predicted Structures and Dynamics for Agonists and Antagonists Bound to Serotonin 5-HT2B and 5-HT2C Receptors

Subtype 2 serotonin (5-hydroxytryptamine, 5-HT) receptors are major drug targets for schizophrenia, feeding disorders, perception, depression, migraines, hypertension, anxiety, hallucinogens, and gastrointestinal dysfunctions.' We report here the predicted structure of 5-HT2B and 5-HT2C receptors bound to highly potent and selective 5-HT2B antagonist PRX-08066 3, (pKi: 30 nM), including the key binding residues [V103 (2.53), L132 (3.29), V190 (4.60), and L347 (6.58)] determining the selectivity of binding to 5-HT2B over 5-HT2A. We also report structures of the endogenous agonist (5 HT) and a HT2B selective antagonist 2 (1-methyl-1-1,6,7,8-tetrahydro-pyrrolo [2,3-g]quinoline-5-carboxylic acid pyridine-3-ylamide). We examine the dynamics for the agonist-and antagonist-bound HT2B receptors in explicit membrane and water finding dramatically different patterns of water migration into the NPxxY motif and the binding site that correlates with the stability of ionic locks in the D(E)RY region.